SUMMARY
K. Sreekumaran (Sree) Nair, M.D., Ph.D., is an endocrinologist whose research explores how insulin regulates energy metabolism and proteome homeostasis. Dr. Nair studies how disruptions in these processes contribute to aging and diabetes and related metabolic disorders.
Dr. Nair and his team study the effects of insulin deficiency and insulin resistance on skeletal muscle and the brain, with particular emphasis on mitochondrial function, energy production and oxidative stress. Dr. Nair's research also examines how exercise and therapeutic interventions may improve metabolic health and preserve tissue function. Dr. Nair receives funding from the National Institutes of Health (NIH) to help support his research efforts.
Dr. Nair's long-term research goal is to identify approaches that prevent or reverse metabolic dysfunction and its complications.
Focus areas
Insulin regulation of energy metabolism and proteostasis
Dr. Nair and his team study how insulin deficiency and insulin resistance affect mitochondrial function, energy production and proteome homeostasis in skeletal muscle and the brain.
Their research has shown that transient insulin deprivation increases fuel oxidation in skeletal muscle while reducing ATP production and increasing reactive oxygen species. These changes can contribute to oxidative stress and impaired cellular function.
The team also studies how the brain responds differently to insulin deficiency by increasing transport of alternative fuels such as ketones and lactate. This work examines whether mitochondrial alterations associated with insulin resistance can be prevented or reversed through physiological and therapeutic interventions.
Molecular mechanisms of exercise benefits for insulin resistance
Dr. Nair leads research on how aerobic exercise, resistance training and combined exercise training affect skeletal muscle structure and function in people with insulin resistance. The team also studies the effects on brain bioenergetics, structure, functional connectivity and cognition.
Using mass spectrometry-based proteomics, phosphoproteomics, acetylomics and metabolomics, Dr. Nair's team has identified distinct molecular signatures associated with different exercise-training modes and improvements in cardiometabolic risk factors. Recent work has also examined differences in exercise responses by biological sex and sex hormones. The team has also applied transcranial magnetic stimulation to study brain-skeletal muscle connectivity.
Metformin effect on brain function in insulin resistance
A major focus of Dr. Nair's NIH-supported research is how insulin resistance affects brain bioenergetics, regional connectivity, structure and cognition in older adults.
His team uses MRI, functional MRI, phosphorus MR spectroscopy, FDG-PET and neurobehavioral assessment to study the effects of insulin resistance on the brain. A randomized, placebo-controlled trial in older adults with insulin resistance is evaluating whether metformin enhances brain mitochondrial function, regional connectivity and cognition.
The team also is investigating other pharmacological approaches that may help prevent damage to the brain and cognition related to insulin resistance.
Glucagon and catabolic metabolism
Dr. Nair and his team study the thermogenic and catabolic effects of glucagon beyond its established role in gluconeogenesis. Their work has shown that increased fuel oxidation during insulin deficiency is related to hyperglucagonemia and that glucagon has protein-catabolic effects, including in skeletal muscle.
The team investigates regional effects and interorgan communication associated with excess glucagon and resulting abnormalities in amino acid and energy metabolism. These studies use arteriovenous balance methods, animal models, cell culture, stable isotopes and mass spectrometry-based approaches. This work is increasingly relevant since glucagon receptor agonists are used to treat type 2 diabetes and obesity.
Extracellular vesicles and metabolic health
Dr. Nair's team has developed a size-exclusion-based method to purify small extracellular vesicles from human plasma and uses proteomic and transcriptomic profiling to characterize their molecular cargo. The researchers investigate how exercise training changes the abundance and cargo of these vesicles and whether the changes help mediate communication among skeletal muscle, liver and brain.
This work complements the team's exercise and brain research by examining how the systemic benefits of exercise may be communicated at the molecular level through circulating vesicles.
Significance to patient care
Dr. Nair's research helps doctors understand the metabolic basis of diabetes and aging so that patient care can be improved.
Professional highlights
- Mayo Clinic:
- Dr. Richard F. Emslander Professor of Endocrinology and Nutrition Research 1, 2020-present.
- Pioneering Research Award in Medicine, 2025.
- Outstanding Mentor Award, Department of Medicine, 2011.
- Directors Award, Outstanding Contributions to Aging Research, Robert and Arlene Kogod Center on Aging, 2006.
- Distinguished Investigator Award, 2005.
- Dorothy Hodgkin Lecture, Diabetes UK, 2024.
- European Society for Clinical Nutrition and Metabolism:
- Honorary member for lifetime achievement, 2016.
- Cuthbertson Lecture Award, 2010.
- Philip J. Garry/Robert E. Labbe Award, Outstanding Contributions, Association for Diagnostics and Laboratory Medicine (ADLM), 2011.
- Honorary Knighthood of Horse Collar, honoring seminal contributions to exercise physiology, Finland, 2011.
- Honorary doctorate and adjunct professorship in medicine, Karolinska Institutet, 2008.
- Takeda Lecture on Aging and Diabetes, The Japan Geriatrics Society, 2008.
- E.V. McCollum Award, American Society for Nutrition, 2003.